细胞周期蛋白依赖激酶2
细胞周期蛋白依赖激酶
癌症研究
视网膜母细胞瘤蛋白
细胞周期蛋白依赖激酶4
细胞周期
激酶
CDK抑制剂
细胞周期蛋白E1
生物
乳腺癌
细胞周期蛋白依赖激酶6
癌症
细胞生物学
蛋白激酶A
遗传学
作者
Catherine Dietrich,Alec Trub,Antonio Ahn,Michael Taylor,Krutika Ambani,Keefe T. Chan,Kun-Hui Lu,Christabella A. Mahendra,Catherine Blyth,Rhiannon Coulson,Susanne Ramm,April C. Watt,Sunil Kumar Matsa,John E. Bisi,Jay C. Strum,Patrick Roberts,Shom Goel
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2023-12-04
被引量:1
标识
DOI:10.1158/2159-8290.cd-23-0954
摘要
Abstract Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring CCNE1 amplification and breast cancers that have acquired resistance to CDK4/6 inhibitors (CDK4/6i). The precise impact of pharmacological inhibition of CDK2 is not known due to the lack of selective CDK2 inhibitors. Here we describe INX-315, a novel and potent CDK2 inhibitor with high selectivity over other CDK family members. Using cell-based assays, patient-derived xenografts, and transgenic mouse models, we show that INX-315 (i) promotes retinoblastoma protein hypo-phosphorylation and therapy-induced senescence (TIS) in CCNE1-amplified tumors, leading to durable control of tumor growth; (ii) overcomes breast cancer resistance to CDK4/6i, restoring cell cycle control whilst re-instating the chromatin architecture of CDK4/6i-induced TIS; and (iii) delays the onset of CDK4/6i resistance in breast cancer by driving deeper suppression of E2F targets. Our results support the clinical development of selective CDK2 inhibitors.
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